Chemotherapeutic agents are an effective means to treat cancer, particularly when the agent is well-suited to target the specific direct or indirect molecular origin of the disease. However, in some cases, resistance to one or more chemotherapeutic agents manifests during treatment, and sometimes a particular agent becomes wholly ineffective in certain individuals. In some embodiments, this resistance may derive from mutations that arise in a particular gene directly or indirectly associated with the cancer. Although resistance to chemotherapeutic agents has occurred in a wide variety of cancers, the present invention, in particular embodiments, regards resistance to chemotherapeutic agents that provide therapy for gastrointestinal stromal tumors (GISTs).
GISTs originate from transformation of interstitial cells of Cajal, a network of innervated cells that coordinate peristalsis in the gastrointestinal system. Aberrant KIT signal represent the initiating event in the pathogenesis of GISTs and KIT gain of function mutations have been reported (Hirota et al., 1998; Lux et al., 2000; Lasota et al., 2000; Corless et al., 2002; Rubin et al., 2001; Sandberg and Bridge, 2002; Heinrich et al., 2002; Koh et al., 2004). Microarray analysis showed that GISTs exhibit a remarkably homogeneous gene expression profile unlike the extremely heterogeneous patterns seen in common epithelial cancers (Allander et al., 2001). KIT with an exon 11 mutation that replaced Lys558 with Val (Lys558Val) was introduced by knock-in strategy, and that produced tumors indistinguishable from human GISTs (Sommer et al., 2003). These results indicate that constitutive KIT signaling is both critical and sufficient for GIST.
The locations of KIT mutations are nonrandom and vary according to cell lineage. KIT exon 11 is the most frequent mutation site for GISTs (Hirota et al., 1998; Lux et al. 2000; Lasota et al., 2000; Corless et al., 2002; Rubin et al., 2001), most commonly clustered in the cytoplasmic juxtamembrane region between 550 and 563, resulting in pathological release from autoinhibition (Ma et al., 1999; Chan et al., 2003) and constitutive activation of KIT. Mutations in exon 9 make up 3% to 21% of all cases (Lasota et al., 2000; Rubin et al., 2001; Hirota et al., 2001). Mutation in exon 13 is rare; to date there are only five reported cases (Lux et al., 2000; Lasota et al., 2000; Sakurai et al., 2001; Kinoshita et al., 2003), all exhibiting the same 1945A→G, Glu642Lys mutation which is 12 amino acids N-terminal to a novel mutation provided herein. Exon 17 mutation is extremely rare in GISTs with only three reported cases so far, two sporadic cases with Asn822His and Asn822Lys (Heinrich et al., 2003) and one Asp820Tyr mutation in a patient with familial GIST with dysphagia (Hirota et al., 2002). GISTs with wild type KIT (Rubin et al., 2001; Heinrich et al., 2003; Hirota et al., 2003) range from 8-35% of cases and often have PDGFR α activating mutation (Heinrich et al., 2003; Hirota et al. 2003). Imatinib (also referred to as imatinib mesylate, gleevec, glivec, or STI571) (Fabbro et al., 2002; Manley et al., 2002) is a selective ATP-competitive inhibitor of KIT, BCR-ABL, and PDGFRα and β and is the only drug effective against GISTs (Demetri et al., 2002; Kitamura et al., 2003; Heinrich et al., 2003; Joensuu et al., 2001; Dei Tos, 2003; van Oosterom et al., 2001). Imatinib revolutionized the care of GIST patients and represents a new paradigm of targeted cancer chemotherapy. Unfortunately, imatinib resistance has begun to emerge. Elucidation of one or more drug resistance mechanisms, especially, for an extremely effective selective tyrosine kinase inhibitor like imatinib should provide new insights in reversing drug resistance and identifying new targets for cancer therapy.
Tuveson et al. (2001) describe a homozygous exon 13 missense mutation in c-KIT at K642E utilized to establish a human GIST cell line. Although the KIT protein was constitutively tyrosine phosphorylated, this phosphorylation was abolished after introducing STI571 to the cells.
US 2004/0005623 regards assessment of whether a specific drug that can inhibit one form of a tumor expressing activated KIT protein can also interact with and treat other tumors. In particular embodiments, the interaction between a drug and enzyme from a patient tumor is determined through analysis of nucleotide sequence of at least part of a c-KIT allele.